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Acta Pharmaceutica Sinica. B Jan 2022Metabolic homeostasis requires dynamic catabolic and anabolic processes. Autophagy, an intracellular lysosomal degradative pathway, can rewire cellular metabolism... (Review)
Review
Metabolic homeostasis requires dynamic catabolic and anabolic processes. Autophagy, an intracellular lysosomal degradative pathway, can rewire cellular metabolism linking catabolic to anabolic processes and thus sustain homeostasis. This is especially relevant in the liver, a key metabolic organ that governs body energy metabolism. Autophagy's role in hepatic energy regulation has just begun to emerge and autophagy seems to have a much broader impact than what has been appreciated in the field. Though classically known for selective or bulk degradation of cellular components or energy-dense macromolecules, emerging evidence indicates autophagy selectively regulates various signaling proteins to directly impact the expression levels of metabolic enzymes or their upstream regulators. Hence, we review three specific mechanisms by which autophagy can regulate metabolism: A) nutrient regeneration, B) quality control of organelles, and C) signaling protein regulation. The plasticity of the autophagic function is unraveling a new therapeutic approach. Thus, we will also discuss the potential translation of promising preclinical data on autophagy modulation into therapeutic strategies that can be used in the clinic to treat common metabolic disorders.
PubMed: 35127371
DOI: 10.1016/j.apsb.2021.07.021 -
Endocrine Reviews Aug 2020Adrenoleukodystrophy (ALD) is a rare X-linked disorder of peroxisomal oxidation due to mutations in ABCD1. It is a progressive condition with a variable clinical... (Review)
Review
Adrenoleukodystrophy (ALD) is a rare X-linked disorder of peroxisomal oxidation due to mutations in ABCD1. It is a progressive condition with a variable clinical spectrum that includes primary adrenal insufficiency, myelopathy, and cerebral ALD. Adrenal insufficiency affects over 80% of ALD patients. Cerebral ALD affects one-third of boys under the age of 12 and progresses to total disability and death without treatment. Hematopoietic stem cell transplantation (HSCT) remains the only disease-modifying therapy if completed in the early stages of cerebral ALD, but it does not affect the course of adrenal insufficiency. It has significant associated morbidity and mortality. A recent gene therapy clinical trial for ALD reported short-term MRI and neurological outcomes comparable to historical patients treated with HSCT without the associated adverse side effects. In addition, over a dozen states have started newborn screening (NBS) for ALD, with the number of states expecting to double in 2020. Genetic testing of NBS-positive neonates has identified novel variants of unknown significance, providing further opportunity for genetic characterization but also uncertainty in the monitoring and therapy of subclinical and/or mild adrenal insufficiency or cerebral involvement. As more individuals with ALD are identified at birth, it remains uncertain if availability of matched donors, transplant (and, potentially, gene therapy) centers, and specialists may affect the timely treatment of these individuals. As these promising gene therapy trials and NBS transform the clinical management and outcomes of ALD, there will be an increasing need for the endocrine management of presymptomatic and subclinical adrenal insufficiency. (Endocrine Reviews 41: 1 - 17, 2020).
Topics: Adrenal Insufficiency; Adrenoleukodystrophy; Genetic Testing; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Infant, Newborn; Male; Neonatal Screening
PubMed: 32364223
DOI: 10.1210/endrev/bnaa013 -
International Journal of Developmental... Feb 2020Adrenoleukodystrophy (ALD) is a rare X-linked disease caused by a mutation of the peroxisomal ABCD1 gene. This review summarizes our current understanding of the... (Review)
Review
Adrenoleukodystrophy (ALD) is a rare X-linked disease caused by a mutation of the peroxisomal ABCD1 gene. This review summarizes our current understanding of the pathogenic cell- and tissue-specific roles of lipid species in the context of experimental therapeutic strategies and provides an overview of critical historical developments, therapeutic trials and the advent of newborn screening in the USA. In ALD, very long-chain fatty acid (VLCFA) chain length-dependent dysregulation of endoplasmic reticulum stress and mitochondrial radical generating systems inducing cell death pathways has been shown, providing the rationale for therapeutic moiety-specific VLCFA reduction and antioxidant strategies. The continuing increase in newborn screening programs and promising results from ongoing and recent therapeutic investigations provide hope for ALD.
Topics: ATP Binding Cassette Transporter, Subfamily D, Member 1; Adrenoleukodystrophy; Endoplasmic Reticulum Stress; Humans; Infant, Newborn; Mutation; Neonatal Screening
PubMed: 31909500
DOI: 10.1002/jdn.10003 -
Autophagy Feb 2021The structural integrity and functional stability of organelles are prerequisites for the viability and responsiveness of cells. Dysfunction of multiple organelles is... (Review)
Review
The structural integrity and functional stability of organelles are prerequisites for the viability and responsiveness of cells. Dysfunction of multiple organelles is critically involved in the pathogenesis and progression of various diseases, such as chronic obstructive pulmonary disease, cardiovascular diseases, infection, and neurodegenerative diseases. In fact, those organelles synchronously present with evident structural derangement and aberrant function under exposure to different stimuli, which might accelerate the corruption of cells. Therefore, the quality control of multiple organelles is of great importance in maintaining the survival and function of cells and could be a potential therapeutic target for human diseases. Organelle-specific autophagy is one of the major subtypes of autophagy, selectively targeting different organelles for quality control. This type of autophagy includes mitophagy, pexophagy, reticulophagy (endoplasmic reticulum), ribophagy, lysophagy, and nucleophagy. These kinds of organelle-specific autophagy are reported to be beneficial for inflammatory disorders by eliminating damaged organelles and maintaining homeostasis. In this review, we summarized the recent findings and mechanisms covering different kinds of organelle-specific autophagy, as well as their involvement in various diseases, aiming to arouse concern about the significance of the quality control of multiple organelles in the treatment of inflammatory diseases. ABCD3: ATP binding cassette subfamily D member 3; AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; AMBRA1: autophagy and beclin 1 regulator 1; AMPK: AMP-activated protein kinase; ARIH1: ariadne RBR E3 ubiquitin protein ligase 1; ATF: activating transcription factor; ATG: autophagy related; ATM: ATM serine/threonine kinase; BCL2: BCL2 apoptosis regulator; BCL2L11/BIM: BCL2 like 11; BCL2L13: BCL2 like 13; BECN1: beclin 1; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CANX: calnexin; CAT: catalase; CCPG1: cell cycle progression 1; CHDH: choline dehydrogenase; COPD: chronic obstructive pulmonary disease; CSE: cigarette smoke exposure; CTSD: cathepsin D; DDIT3/CHOP: DNA-damage inducible transcript 3; DISC1: DISC1 scaffold protein; DNM1L/DRP1: dynamin 1 like; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; EIF2S1/eIF2α: eukaryotic translation initiation factor 2 alpha kinase 3; EMD: emerin; EPAS1/HIF-2α: endothelial PAS domain protein 1; ER: endoplasmic reticulum; ERAD: ER-associated degradation; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; FBXO27: F-box protein 27; FKBP8: FKBP prolyl isomerase 8; FTD: frontotemporal dementia; FUNDC1: FUN14 domain containing 1; G3BP1: G3BP stress granule assembly factor 1; GBA: glucocerebrosidase beta; HIF1A/HIF1: hypoxia inducible factor 1 subunit alpha; IMM: inner mitochondrial membrane; LCLAT1/ALCAT1: lysocardiolipin acyltransferase 1; LGALS3/Gal3: galectin 3; LIR: LC3-interacting region; LMNA: lamin A/C; LMNB1: lamin B1; LPS: lipopolysaccharide; MAPK8/JNK: mitogen-activated protein kinase 8; MAMs: mitochondria-associated membranes; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MFN1: mitofusin 1; MOD: multiple organelles dysfunction; MTPAP: mitochondrial poly(A) polymerase; MUL1: mitochondrial E3 ubiquitin protein ligase 1; NBR1: NBR1 autophagy cargo receptor; NLRP3: NLR family pyrin domain containing 3; NUFIP1: nuclear FMR1 interacting protein 1; OMM: outer mitochondrial membrane; OPTN: optineurin; PD: Parkinson disease; PARL: presenilin associated rhomboid like; PEX3: peroxisomal biogenesis factor 3; PGAM5: PGAM family member 5; PHB2: prohibitin 2; PINK1: PTEN induced putative kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RETREG1/FAM134B: reticulophagy regulator 1; RHOT1/MIRO1: ras homolog family member T1; RIPK3/RIP3: receptor interacting serine/threonine kinase 3; ROS: reactive oxygen species; RTN3: reticulon 3; SEC62: SEC62 homolog, preprotein translocation factor; SESN2: sestrin2; SIAH1: siah E3 ubiquitin protein ligase 1; SNCA: synuclein alpha; SNCAIP: synuclein alpha interacting protein; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; TICAM1/TRIF: toll-like receptor adaptor molecule 1; TIMM23: translocase of inner mitochondrial membrane 23; TNKS: tankyrase; TOMM: translocase of the outer mitochondrial membrane; TRIM: tripartite motif containing; UCP2: uncoupling protein 2; ULK1: unc-51 like autophagy activating kinase; UPR: unfolded protein response; USP10: ubiquitin specific peptidase 10; VCP/p97: valosin containing protein; VDAC: voltage dependent anion channels; XIAP: X-linked inhibitor of apoptosis; ZNHIT3: zinc finger HIT-type containing 3.
Topics: Autophagy; Endoribonucleases; Humans; Inflammation; Mitophagy; Organelles; Prohibitins; Quality Control
PubMed: 32048886
DOI: 10.1080/15548627.2020.1725377 -
Physiological Reviews Jan 2023Peroxisomes are subcellular organelles that play a central role in human physiology by catalyzing a range of unique metabolic functions. The importance of peroxisomes... (Review)
Review
Peroxisomes are subcellular organelles that play a central role in human physiology by catalyzing a range of unique metabolic functions. The importance of peroxisomes for human health is exemplified by the existence of a group of usually severe diseases caused by an impairment in one or more peroxisomal functions. Among others these include the Zellweger spectrum disorders, X-linked adrenoleukodystrophy, and Refsum disease. To fulfill their role in metabolism, peroxisomes require continued interaction with other subcellular organelles including lipid droplets, lysosomes, the endoplasmic reticulum, and mitochondria. In recent years it has become clear that the metabolic alliance between peroxisomes and other organelles requires the active participation of tethering proteins to bring the organelles physically closer together, thereby achieving efficient transfer of metabolites. This review intends to describe the current state of knowledge about the metabolic role of peroxisomes in humans, with particular emphasis on the metabolic partnership between peroxisomes and other organelles and the consequences of genetic defects in these processes. We also describe the biogenesis of peroxisomes and the consequences of the multiple genetic defects therein. In addition, we discuss the functional role of peroxisomes in different organs and tissues and include relevant information derived from model systems, notably peroxisomal mouse models. Finally, we pay particular attention to a hitherto underrated role of peroxisomes in viral infections.
Topics: Animals; Humans; Mice; Peroxisomes
PubMed: 35951481
DOI: 10.1152/physrev.00051.2021 -
Best Practice & Research. Clinical... Aug 2020Systemic autoinflammatory diseases (SAIDs) are defined as disorders of innate immunity. They were initially defined in opposition to autoimmune diseases due to the lack... (Review)
Review
Systemic autoinflammatory diseases (SAIDs) are defined as disorders of innate immunity. They were initially defined in opposition to autoimmune diseases due to the lack of involvement of the adaptive immune system and circulating autoantibodies. The four historical monogenic diseases are familial Mediterranean fever (associated with MEFV mutations), cryopyrinopathies (NLRP3 mutations), tumor necrosis factor receptor-associated periodic syndrome (TNFRSF1A mutations), and mevalonate kinase deficiency (MVK mutations). In the last 10 years, more than 50 new monogenic SAIDs have been discovered thanks to advances in genetics. Diagnosis is largely based on personal and family history and detailed analysis of signs and symptoms associated with febrile attacks, in the setting of elevated inflammatory markers. Increasingly efficient techniques of genetic analysis can contribute to refining the diagnosis. This review is a guide for the clinician in suspecting and establishing a diagnosis of SAID.
Topics: Cryopyrin-Associated Periodic Syndromes; Familial Mediterranean Fever; Fever; Hereditary Autoinflammatory Diseases; Humans; Mevalonate Kinase Deficiency; Pyrin
PubMed: 32546426
DOI: 10.1016/j.berh.2020.101529 -
Frontiers in Neurology 2021Metabolic diseases should always be considered when evaluating children presenting with seizures. This is because many metabolic disorders are potentially treatable and... (Review)
Review
Metabolic diseases should always be considered when evaluating children presenting with seizures. This is because many metabolic disorders are potentially treatable and seizure control can be achieved when these diseases are appropriately treated. Seizures caused by underlying metabolic diseases (metabolic seizures) should be particularly considered in unexplained neonatal seizures, refractory seizures, seizures related to fasting or food intake, seizures associated with other systemic or neurologic features, parental consanguinity, and family history of epilepsy. Metabolic seizures can be caused by various amino acids metabolic disorders, disorders of energy metabolism, cofactor-related metabolic diseases, purine and pyrimidine metabolic diseases, congenital disorders of glycosylation, and lysosomal and peroxisomal disorders. Diagnosing metabolic seizures without delay is essential because the immediate initiation of appropriate therapy for many metabolic diseases can prevent or minimize complications.
PubMed: 34295297
DOI: 10.3389/fneur.2021.640371 -
Neurology Nov 2022Pathogenic variants in the gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by 3 core clinical syndromes: a slowly progressive...
Pathogenic variants in the gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by 3 core clinical syndromes: a slowly progressive myeloneuropathy, a rapidly progressive inflammatory leukodystrophy (cerebral ALD), and primary adrenal insufficiency. These syndromes are not present in all individuals and are not related to genotype. Cerebral ALD and adrenal insufficiency require early detection and intervention and warrant clinical surveillance because of variable penetrance and age at onset. Newborn screening has increased the number of presymptomatic individuals under observation, but clinical surveillance protocols vary. We used a consensus-based modified Delphi approach among 28 international ALD experts to develop best-practice recommendations for diagnosis, clinical surveillance, and treatment of patients with ALD. We identified 39 discrete areas of consensus. Regular monitoring to detect the onset of adrenal failure and conversion to cerebral ALD is recommended in all male patients. Hematopoietic cell transplant (HCT) is the treatment of choice for cerebral ALD. This guideline addresses a clinical need in the ALD community worldwide as the number of overall diagnoses and presymptomatic individuals is increasing because of newborn screening and greater availability of next-generation sequencing. The poor ability to predict the disease course informs current monitoring intervals but remains subject to change as more data emerge. This knowledge gap should direct future research and illustrates once again that international collaboration among physicians, researchers, and patients is essential to improving care.
Topics: Infant, Newborn; Humans; Male; Adrenoleukodystrophy; Consensus; Hematopoietic Stem Cell Transplantation; Adrenal Insufficiency; Neonatal Screening
PubMed: 36175155
DOI: 10.1212/WNL.0000000000201374 -
Science Translational Medicine Dec 2020Nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) has reached epidemic proportions with no pharmacological therapy approved. Lower...
Nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) has reached epidemic proportions with no pharmacological therapy approved. Lower circulating glycine is consistently reported in patients with NAFLD, but the causes for reduced glycine, its role as a causative factor, and its therapeutic potential remain unclear. We performed transcriptomics in livers from humans and mice with NAFLD and found suppression of glycine biosynthetic genes, primarily alanine-glyoxylate aminotransferase 1 (). Genetic ( mice) and dietary approaches to limit glycine availability resulted in exacerbated diet-induced hyperlipidemia and steatohepatitis, with suppressed mitochondrial/peroxisomal fatty acid β-oxidation (FAO) and enhanced inflammation as the underlying pathways. We explored glycine-based compounds with dual lipid/glucose-lowering properties as potential therapies for NAFLD and identified a tripeptide (Gly-Gly-L-Leu, DT-109) that improved body composition and lowered circulating glucose, lipids, transaminases, proinflammatory cytokines, and steatohepatitis in mice with established NASH induced by a high-fat, cholesterol, and fructose diet. We applied metagenomics, transcriptomics, and metabolomics to explore the underlying mechanisms. The bacterial genus sensu stricto was markedly increased in mice with NASH and decreased after DT-109 treatment. DT-109 induced hepatic FAO pathways, lowered lipotoxicity, and stimulated de novo glutathione synthesis. In turn, inflammatory infiltration and hepatic fibrosis were attenuated via suppression of NF-κB target genes and TGFβ/SMAD signaling. Unlike its effects on the gut microbiome, DT-109 stimulated FAO and glutathione synthesis independent of NASH. In conclusion, impaired glycine metabolism may play a causative role in NAFLD. Glycine-based treatment attenuates experimental NAFLD by stimulating hepatic FAO and glutathione synthesis, thus warranting clinical evaluation.
Topics: Animals; Diet, High-Fat; Fatty Acids; Gastrointestinal Microbiome; Glutathione; Glycine; Humans; Liver; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease
PubMed: 33268508
DOI: 10.1126/scitranslmed.aaz2841